Interval therapy for the treatment of tinnitus

ABSTRACT

The present invention relates to interval and/or maintenance therapy employing 1-amino-alkylcyclohexane derivatives (e.g., neramexane or a pharmaceutically acceptable salt thereof) for the treatment of an individual afflicted with tinnitus.

FIELD OF THE INVENTION

The present invention relates to interval and/or maintenance therapyemploying 1-amino-alkylcyclohexane derivatives (e.g., neramexane or apharmaceutically acceptable salt thereof) for the treatment of anindividual afflicted with tinnitus.

BACKGROUND OF THE INVENTION

Tinnitus is commonly referred to as ‘ringing in the ears’—the perceptionof sounds in the absence of an external source of acoustic signals.Tinnitus has been defined as “the perception of a sound which resultsexclusively from the activity within the nervous system without anycorresponding mechanical, vibratory activity within the cochlea, thatis, tinnitus as an auditory phantom perception” (Jastreboff et al., J AmAcad Audiol 2000; 11(3): 162-177). Tinnitus is frequently associatedwith a decreased sound tolerance (i.e. hyperacusis).

The pathophysiology of subjective tinnitus is poorly understood and adefinitive pathogenesis of tinnitus is unknown. Many environmental andsubstance-induced factors may cause tinnitus. Among the most frequentlycited factors are acute acoustic trauma, occupational noise, andrecreational music. In general, tinnitus seems to be the result ofneuronal dysfunction within the auditory pathway. This dysfunction ismisleadingly perceived as sound by higher auditory centers and can leadto functional alterations within the auditory nervous system.Maladaptive functional changes in cortical structures could result in analtered balance between excitatory and inhibitory neurotransmission andmay lead to more severe tinnitus. In all cases, a potential malfunctionin auditory pathways and auditory cortex is related to the activity ofthe prefrontal cortex and limbic system.

In most cases (95%), the perceived tinnitus is purely subjective innature, e.g. no physical source of acoustic signals can be identifiedand, therefore, cannot be heard externally. A physical examination isperformed to exclude objective tinnitus, e.g. the patient's perceptionof sound is caused by a real source of sound waves, e.g. the sound fromturbulent flow in blood vessels reaching the cochlea. Tinnitus may beclassified according to duration of tinnitus and the degree of tinnitusexpression (e.g. severity or annoyance of the tinnitus) (McCombe et al.,Clin Otolaryngol 2001; 26(5): 388-393 and Davis et al., Epidemiology ofTinnitus. In: Tyler R, editor. Tinnitus Handbook. San Diego: SingularPublishing Group; 2000. p. 1-23). Regarding the impact of tinnitus,tinnitus may be severely annoying to the patient and may be accompaniedby social and psychological complications.

There are currently no well-established, specific medical treatments fortinnitus that provide replicable reduction of tinnitus and annoyance dueto tinnitus, in excess of placebo effects (Dobie, Laryngoscope 1999;109(8): 1202-1211; Eggermont et al., Trends Neurosci 2004; 27(11):676-682; and Patterson et al., Int Tinnitus J 2006; 12(2): 149-159).Thus, a need exists for pharmaceutical products and therapies which areeffective in treating or preventing tinnitus. Huynh, et al. (AnnPharmacother 1995; 29(3): 311-312) also disclose that there is a needfor investigating the necessity of a maintenance therapy as well as therole of treatment-free intervals (“drug-holidays’) in the development ofnew tinnitus medications.

1-Amino-alkylcyclohexanes such as neramexane (also known as1-amino-1,3,3,5,5-pentamethylcyclohexane) have been found to be usefulin the therapy of various diseases especially in certain neurologicaldiseases, including Alzheimer's disease and neuropathic pain.1-Amino-alkylcyclohexanes such as neramexane are disclosed in detail inU.S. Pat. Nos. 6,034,134 and 6,071,966, the subject matter of whichpatents is hereby incorporated by reference. It is believed that thetherapeutic action of 1-amino-alkylcyclohexanes such as neramexane isrelated to the inhibition of the effects of excessive glutamate at theN-methyl-D-aspartate (NMDA) receptors of nerve cells, for which reasonthe compounds are also categorized as NMDA antagonists, or NMDA receptorantagonists. Neramexane has also been disclosed to exhibit activity asan α 9/α 10 nicotinic receptor antagonist (Plazas, et al., Eur J.Pharmacol., 2007 Jul. 2; 566 (1-3):11-19).

U.S. Pat. No. 6,034,134 discloses that 1-amino-alkylcyclohexanes may beuseful in the treatment of tinnitus due to their activity as NMDAreceptor antagonists.

The instant inventors have discovered that interval and/or maintenancetherapy employing 1-amino-alkylcyclohexanes, such as neramexane or apharmaceutically acceptable salt thereof, may be an effective approachfor the treatment of tinnitus.

Maintenance treatment may prevent recurrence of tinnitus in patientswith sufficient or stable treatment effects through administering thereduced dose of an 1-amino-alkylcyclohexane derivative (e.g., neramexaneor a pharmaceutically acceptable salt thereof such as neramexanemesylate).

A benefit associated with such treatment is a significantly reduced drugexposure while the anti-tinnitus effect is still sufficient.

If tinnitus re-occurs the chance for sufficient treatment effect with1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate)may be lower than at first onset since irreversible changes in theauditory system may have time to progress and become chronic.

However, if tinnitus symptoms re-occur in patients receiving maintenancetreatment (e.g., 20-75% of the therapeutically effective dose) therelapse may be milder and may respond more sensitively to an immediateincrease of the 1-amino-alkylcyclohexane derivative (e.g., neramexane ora pharmaceutically acceptable salt thereof such as neramexane mesylate)dose to a therapeutically effective dose (e.g. 25 mg neramexane mesylateb.i.d. or 37.5 mg b.i.d. for subjects heavier then 90 kg bodyweight)than in patients without maintenance treatment.

SUMMARY OF THE INVENTION

The present invention relates to a 1-amino-alkylcyclohexane derivativefor the treatment of tinnitus, wherein a therapeutically effectiveamount of the 1-amino-alkylcyclohexane derivative is administered dailyfor a first period of at least three (3) months, followed by a secondperiod of at least one (1) month wherein the 1-amino-alkylcyclohexanederivative is administered at a dose which is 0-75% of thetherapeutically effective dose.

A further aspect the invention relates to the use of a1-amino-alkylcyclohexane derivative for the manufacture of a medicamentfor treating tinnitus in a subject in need thereof, wherein atherapeutically effective amount of the 1-amino-alkylcyclohexanederivative is administered daily for a first period of at least three(3) months, followed by a second period of at least one (1) monthwherein the 1-amino-alkylcyclohexane derivative is administered at adose which is 0-75% of the therapeutically effective dose.

A further aspect the invention relates to a 1-amino-alkylcyclohexanederivative for the treatment of a 1-amino-alkylcyclohexane derivativeresponsive condition in a subject in need thereof wherein atherapeutically effective amount of the 1-amino-alkylcyclohexanederivative is administered to said subject daily for a first period ofat least three (3) months, followed by a second period of at least one(1) month wherein the 1-amino-alkylcyclohexane derivative isadministered at a dose which is 0-75% of the therapeutically effectivedose.

A further aspect the invention relates to the use of a1-amino-alkylcyclohexane derivative for the manufacture of a medicamentfor the treatment of a 1-amino-alkylcyclohexane derivative responsivecondition in a subject in need thereof wherein a therapeuticallyeffective amount of the 1-amino-alkylcyclohexane derivative isadministered to said subject daily for a first period of at least three(3) months, followed by a second period of at least one (1) monthwherein the 1-amino-alkylcyclohexane derivative is administered at adose which is 0-75% of the therapeutically effective dose.

The 1-amino-alkylcyclohexane derivative as well as the medicamentspecified herein are for the administration according to theabove-defined administration scheme. In one embodiment, thederivative/medicament is specifically adapted to provide the respectiveinformation regarding the administration scheme to the patient. Therespective information regarding the specific administration scheme maybe provided via e.g. the respective information in or on the package,the dosage form, such as the appearance thereof, e.g. via tablet coloror tablet form, and/or the package leaflet and/or the patientinformation.

In a further aspect of the invention the therapeutically effectiveamount of the 1-amino-alkylcyclohexane derivative is administered dailyfor a period of at least three (3) months, followed by a period of atleast one month wherein the 1-amino-alkylcyclohexane derivative isadministered at a dose which is above 0 to 75%, such as 20-75% (e.g.25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70%), or such as 25-50%,of the therapeutically effective dose.

The reduction of the dose of the 1-amino-alkylcyclohexane derivative(e.g., neramexane or a pharmaceutically acceptable salt thereof such asneramexane mesylate) between the administration of the therapeuticallyeffective dose and the administration of 0-75%, such as above 0-75%, or20-75%, such as 25-50%, of the therapeutically effective dose may beperformed stepwise. The dose of 50 mg neramexane mesylate daily may, forexample, be reduced to a dose of 25 mg by 12.5 mg steps, wherein the37.5 mg dose is, for example, administered for at least one week. Thedose of 75 mg neramexane mesylate daily may, for example, be reduced toa dose of 25 mg/day. This may be performed by 12.5 mg steps, wherein the62.5 mg/day, 50 mg/day, and 37.5 mg/day doses may, for example, beadministered for at least one week, respectively. Alternatively, thedose of 75 mg neramexane mesylate daily may, for example, be reduced toa dose of 50 mg/day. This may be performed by 12.5 mg steps, wherein the62.5 mg/day dose may, for example, be administered for at least oneweek. In a further embodiment, the dose of 75 mg neramexane mesylatedaily may, for example, be reduced to a dose of 12.5 mg/day. This may beperformed by 12.5 mg steps, wherein the 62.5 mg/day dose, the 50 mg/daydose, the 37.5 mg/day dose, and the 25 mg/day dose may, respectively,for example, be administered for at least one week.

A further aspect of the invention relates to a treatment regimen for anindividual afflicted with tinnitus, comprising administering to theindividual a therapeutically effective amount of a1-amino-alkylcyclohexane derivative (e.g., neramexane or apharmaceutically acceptable salt thereof such as neramexane mesylate),wherein the therapeutically effective amount of the1-amino-alkylcyclohexane derivative is administered daily for a periodof at least three (3) months, followed by a period of at least one monthwherein the 1-amino-alkylcyclohexane derivative is administered at adose which is 0-75%, such as above 0-75%, or 20-75% or 25-50% of thetherapeutically effective dose, with the treatment regimen beingrepeated after a recurrence of tinnitus.

According to the invention patients who have had a tinnitus relapsecontinue on the therapeutically effective dose for at least threemonths, such as for at least one year, before the dose is reduced to amaintenance dose.

Alternatively, the treatment regimen may be repeated after a specificperiod, such as after administering at a dose which is 0-75%, or above0-75%, or 20-75%, such as 25-50% of the therapeutically effective dosefor a period of from three (3) to six (6) months (e.g. 3, 4, 5, or 6months).

In a further aspect of the invention the therapeutically effectiveamount of the 1-amino-alkylcyclohexane derivative is administered dailyfor a first period of at least three (3) months, followed by a secondperiod of at least one month, such as at least three (3) months, whereinthe 1-amino-alkylcyclohexane derivative is not administered, with thetreatment regimen being repeated after said (second) period, i.e., in athird period the same treatment as in the first period is performed,while in the fourth period (as in the second period) no1-amino-alkylcyclohexane derivative is administered. Said order ofperiods with and without treatment can be repeated several times,usually depending upon the progress of the condition within the subjecttreated.

The treatment regimen may be repeated after a specific period, such asafter a period of from three (3) to six (6) months (e.g. 3, 4, 5, or 6months).

According to the invention, the dose reduction, as well as the doseincrease, may be performed stepwise.

According to the invention, previous to the first period ofadministering there may be an initial administering of a dose or dosesin order to increase the dose(s) to reach the therapeutically effectivedose of the first period. If such initial administering is performed, itis usually performed in a stepwise manner (i.e., uptitration).

In a further aspect of the invention a therapeutically effective amountof neramexane or a pharmaceutically acceptable salt thereof, such asneramexane mesylate is administered to the subject, wherein thetherapeutically effective amount of said compound is administered dailyfor a period of at least three (3) months, followed by a period of atleast one (1) month wherein said compound is administered at a dosewhich is 0-75% or above 0-75% of the therapeutically effective dose,with the treatment being repeated as necessary.

In a further aspect of the invention a therapeutically effective amountof neramexane or a pharmaceutically acceptable salt thereof, such asneramexane mesylate is administered to the subject, wherein thetherapeutically effective amount of said compound is administered dailyfor a period of at least three (3) months, followed by a period of atleast one (1) month wherein said compound is administered at a dosewhich is 20-75% of the therapeutically effective dose, with thetreatment regimen being repeated as necessary.

In a further aspect of the invention the therapeutically effectiveamount of neramexane or a pharmaceutically acceptable salt thereof, suchas, neramexane mesylate is administered daily for a period of at leastthree (3) months, followed by a (second) period of at least one (1)month wherein said compound is not administered, with the treatmentregimen being repeated after said (second) period. Said order of periodswith and without treatment can be repeated several times, usuallydepending upon the progress of the condition within the subject treated.

A further aspect of the invention relates to a method of treatingtinnitus in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a 1-amino-alkylcyclohexanederivative, wherein the therapeutically effective amount of the1-amino-alkylcyclohexane derivative is administered daily for a firstperiod of at least three (3) months, followed by a second period of atleast one (1) month wherein the 1-amino-alkylcyclohexane derivative isadministered at a dose which is 0-75% of the therapeutically effectivedose.

A further aspect of the invention relates to such a method whereinduring the second period the 1-amino-alkylcyclohexane derivative isadministered at a dose which is above 0-75% of the therapeuticallyeffective dose.

A further aspect of the invention relates to such a method whereinduring the second period the 1-amino-alkylcyclohexane derivative isadministered at a dose which is 20-75% of the therapeutically effectivedose.

A further aspect of the invention relates to such a method whereinduring the second period the 1-amino-alkylcyclohexane derivative isadministered at a dose which is 25-50% of the therapeutically effectivedose.

A further aspect of the invention relates to such a method whereinduring the second period the 1-amino-alkylcyclohexane derivative is notadministered with treatment being repeated after the second period.

A further aspect of the invention relates to such a method wherein adose increase to reach a therapeutically effective dose following thesecond period is performed stepwise.

A further aspect of the invention relates to such a method wherein thesecond period is followed by administering to the subject atherapeutically effective amount of a 1-amino-alkylcyclohexanederivative after a recurrence of tinnitus.

A further aspect of the invention relates to such a method wherein theadministration of the therapeutically effective amount of a1-amino-alkylcyclohexane derivative after recurrence of tinnitus iscontinued for at least one year.

A further aspect of the invention relates to such a method wherein thesecond period is from three (3) to six (6) months.

A further aspect of the invention relates to such a method whereinbetween the first and second period there is a transition period duringwhich the dose is reduced stepwise.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative is neramexane or a pharmaceuticallyacceptable salt thereof.

A further aspect of the invention relates to such a method wherein the1-amino-alkylcyclohexane derivative is neramexane mesylate.

A further aspect of the invention relates to such a method whereinneramexane mesylate is administered in a range from about 5 mg to about150 mg/day during the first period.

A further aspect of the invention relates to such a method whereinneramexane mesylate is administered in a range from about 5 mg to about100 mg/day.

A further aspect of the invention relates to such a method whereinneramexane mesylate is administered at about 5 mg to about 75 mg/day.

A further aspect of the invention relates to such a method whereinneramexane mesylate is administered at about 50 mg/day.

A further aspect of the invention relates to such a method whereinneramexane mesylate is administered at about 75 mg/day.

A further aspect of the invention relates to such a method whereinneramexane or a pharmaceutically acceptable salt thereof is administeredonce a day, twice a day (b.i.d.), or three times a day.

A further aspect of the invention relates to such a method whereinneramexane or a pharmaceutically acceptable salt thereof is administeredtwice a day.

A further aspect of the invention relates to such a method whereinneramexane or a pharmaceutically acceptable salt thereof is administeredin an immediate release formulation.

A further aspect of the invention relates to such a method whereinneramexane or a pharmaceutically acceptable salt thereof is administeredin a modified release formulation.

A further aspect of the invention relates to a method of treating a1-amino-alkylcyclohexane derivative responsive condition in a subject inneed thereof, comprising administering to the subject a therapeuticallyeffective amount of a 1-amino-alkylcyclohexane derivative, wherein thetherapeutically effective amount of the 1-amino-alkylcyclohexanederivative is administered daily for a first period of at least three(3) months, followed by a second period of at least one (1) monthwherein the 1-amino-alkylcyclohexane derivative is administered at adose which is 0-75% of the therapeutically effective dose.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows data from a tinnitus pilot study with neramexane showingthe change in Tinnitus-Beeinträchtigungs-Fragebogen (TBF-12) (i.e., a12-item the German modified and validated version of the TinnitusHandicap Inventory or THI) score from baseline to all post-baselinevisits.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term tinnitus includes all manifestations ofsubjective and objective tinnitus as well a acute, subacute and chronicforms. It also includes cochlear tinnitus as well as tinnitus associatedwith hearing loss or mild hearing loss.

As used herein, the term hearing loss is synonymous with hearingimpairment and includes several grades of hearing loss (such as mildhearing loss, moderate hearing loss, severe hearing loss, profoundhearing loss, and deafness) as well as several specific forms, such asacoustic trauma, noise-induced hearing loss, sensorineural hearing loss,mixed hearing loss, unspecified hearing loss, ototoxic hearing loss,drug-induced hearing loss, sudden (idiopathic) hearing loss, auditoryprocessing disorder, presbycusis, environmental chemicals-inducedhearing loss, surgery-induced hearing loss, cancer-induced hearing loss,radiation-induced hearing loss, and infection-induced hearing loss.

As used herein, the term subject includes mammals, i.e. animals andhumans.

The term 1-amino-alkylcyclohexane derivative is used herein to describea 1-amino-alkylcyclohexane or a compound derived from1-amino-alkylcyclohexane, e.g., pharmaceutically acceptable salts of1-amino-alkylcyclohexanes. The present 1-amino-alkylcyclohexanederivatives may also be described as “1-aminocyclohexane derivatives.”

The 1-amino-alkylcyclohexane derivatives of the present invention may berepresented by the general formula (I):

wherein R* is —(CH₂)_(n)—(CR⁶R⁷)_(m)—NR⁸R⁹wherein n+m=0, 1, or 2wherein R¹ through R⁷ are independently selected from the groupconsisting of hydrogen and C₁₋₆alkyl, wherein R⁸ and R⁹ areindependently selected from the group consisting of hydrogen andC₁₋₆alkyl or together represent lower-alkylene —(CH₂)_(x)— wherein x is2 to 5, inclusive, and optical isomers, enantiomers, hydrates, andpharmaceutically-acceptable salts thereof.

Non-limiting examples of the 1-amino-alkylcyclohexanes used according tothe present invention include:

-   1-amino-1,3,5-trimethylcyclohexane,-   1-amino-1(trans),3(trans),5-trimethylcyclohexane,-   1-amino-1(cis),3(cis),5-trimethylcyclohexane,-   1-amino-1,3,3,5-tetramethylcyclohexane,-   1-amino-1,3,3,5,5-pentamethylcyclohexane (neramexane),-   1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane,-   1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane,-   1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane,-   1-amino-(1S,5S)cis-3-ethyl-1,5,5-trimethylcyclohexane,-   1-amino-1,5,5-trimethyl-trans-3-ethylcyclohexane,-   1-amino-(1R,5S)trans-3-ethyl-1,5,5-trimethylcyclohexane,-   1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane,-   1-amino-1-propyl-3,3,5,5-tetramethylcyclohexane,-   N-methyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,-   N-ethyl-1-amino-1,3,3,5,5-pentamethyl-cyclohexane,-   N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine,-   3,3,5,5-tetramethylcyclohexylmethylamine,-   1 amino-1,3,3,5(trans)-tetramethylcyclohexane (axial amino group),-   3-propyl-1,3,5,5-tetramethylcyclohexylamine semihydrate,-   1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane,-   1-amino-1,3,5-trimethylcyclohexane,-   1-amino-1,3-dimethyl-3-propylcyclohexane,-   1-amino-1,3(trans),5(trans)-trimethyl-3(cis)-propylcyclohexane,-   1-amino-1,3-dimethyl-3-ethylcyclohexane,-   1-amino-1,3,3-trimethylcyclohexane,-   cis-3-ethyl-1(trans)-3(trans)-5-trimethylcyclohexamine,-   1-amino-1,3(trans)-dimethylcyclohexane,-   1,3,3-trimethyl-5,5-dipropylcyclohexylamine,-   1-amino-1-methyl-3(trans)-propylcyclohexane,-   1-methyl-3(cis)-propylcyclohexylamine,-   1-amino-1-methyl-3(trans)-ethylcyclohexane,-   1-amino-1,3,3-trimethyl-5(cis)-ethylcyclohexane,-   1-amino-1,3,3-trimethyl-5(trans)-ethylcyclohexane,-   cis-3-propyl-1,5,5-trimethylcyclohexylamine,-   trans-3-propyl-1,5,5-trimethylcyclohexylamine,-   N-ethyl-1,3,3,5,5-pentamethylcyclohexylamine,-   N-methyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,-   1-amino-1-methylcyclohexane,-   N,N-dimethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,-   2-(3,3,5,5-tetramethylcyclohexyl)ethylamine,-   2-methyl-1-(3,3,5,5-tetramethylcyclohexyl)propyl-2-amine,-   2-(1,3,3,5,5-pentamethylcyclohexyl)-ethylamine semihydrate,-   N-(1,3,3,5,5-pentamethylcyclohexyl)-pyrrolidine,-   1-amino-1,3(trans),5(trans)-trimethylcyclohexane,-   1-amino-1,3(cis),5(cis)-trimethylcyclohexane,-   1-amino-(1R,5S)trans-5-ethyl-1,3,3-trimethylcyclohexane,-   1-amino-(1S,5S)cis-5-ethyl-1,3,3-trimethylcyclohexane,-   1-amino-1,5,5-trimethyl-3(cis)-isopropyl-cyclohexane,-   1-amino-1,5,5-trimethyl-3(trans)-isopropyl-cyclohexane,-   1-amino-1-methyl-3(cis)-ethyl-cyclohexane,-   1-amino-1-methyl-3(cis)-methyl-cyclohexane,-   1-amino-5,5-diethyl-1,3,3-trimethyl-cyclohexane,-   1-amino-1,3,3,5,5-pentamethylcyclohexane,-   1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane,-   1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane,-   N-ethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,-   N-(1,3,5-trimethylcyclohexyl)pyrrolidine or piperidine,-   N-[1,3(trans),5(trans)-trimethylcyclohexyl]pyrrolidine or    piperidine,-   N-[1,3(cis),5(cis)-trimethylcyclohexyl]pyrrolidine or piperidine,-   N-(1,3,3,5-tetramethylcyclohexyl)pyrrolidine or piperidine,-   N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine or piperidine,-   N-(1,3,5,5-tetramethyl-3-ethylcyclohexyl)pyrrolidine or piperidine,-   N-(1,5,5-trimethyl-3,3-diethylcyclohexyl)pyrrolidine or piperidine,-   N-(1,3,3-trimethyl-cis-5-ethylcyclohexyl)pyrrolidine or piperidine,-   N-[(1S,5S)cis-5-ethyl-1,3,3-trimethylcyclohexyl]pyrrolidine or    piperidine,-   N-(1,3,3-trimethyl-trans-5-ethylcyclohexyl)pyrrolidine or    piperidine,-   N-[(1R,5S)trans-5-ethyl,3,3-trimethylcyclohexyl]pyrrolidine or    piperidine,-   N-(1-ethyl-3,3,5,5-tetramethylyclohexyl)pyrrolidine or piperidine,-   N-(1-propyl-3,3,5,5-tetramethylcyclohexyl)pyrrolidine or piperidine,-   N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine,    and optical isomers, diastereomers, enantiomers, hydrates, their    pharmaceutically acceptable salts, and mixtures thereof.

1-Amino-alkylcyclohexane derivatives (e.g., neramexane,1-amino-1,3,3,5,5-pentamethylcyclohexane) are disclosed in U.S. Pat.Nos. 6,034,134 and 6,071,966. 1-Amino-alkylcyclohexane derivatives(e.g., neramexane) may be used according to the invention in the form ofany of pharmaceutically acceptable salts, solvates, isomers, conjugates,and prodrugs, any references to 1-amino-alkylcyclohexane derivatives(e.g., neramexane) in this description should be understood as alsoreferring to such salts, solvates, isomers, conjugates, and prodrugs.

Pharmaceutically acceptable salts include, but are not limited to, acidaddition salts, such as those made with hydrochloric, methylsulfonic,hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric,acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic,fumaric, tartaric, citric, benzoic, carbonic, cinnamic, mandelic,methanesulfonic, ethanesulfonic, hydroxyethanesulfonic,benezenesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicyclic,p-aminosalicylic, 2-phenoxybenzoic, and 2-acetoxybenzoic acid. All ofthese salts (or other similar salts) may be prepared by conventionalmeans. The nature of the salt is not critical, provided that it isnon-toxic and does not substantially interfere with the desiredpharmacological activity.

The term “analog” or “derivative” is used herein in the conventionalpharmaceutical sense, to refer to a molecule that structurally resemblesa reference molecule (such as neramexane), but has been modified in atargeted and controlled manner to replace one or more specificsubstituents of the referent molecule with an alternate substituent,thereby generating a molecule which is structurally similar to thereference molecule. Synthesis and screening of analogs (e.g., usingstructural and/or biochemical analysis), to identify slightly modifiedversions of a known compound which may have improved or biased traits(such as higher potency and/or selectivity at a specific targetedreceptor type, greater ability to penetrate mammalian blood-brainbarriers, fewer side effects, etc.) is a drug design approach that iswell known in pharmaceutical chemistry.

The term “treat” is used herein to mean to relieve or alleviate at leastone symptom of a disease in a subject. Within the meaning of the presentinvention, the term “treat” also denotes to arrest, delay the onset(i.e., the period prior to clinical manifestation of a disease) and/orreduce the risk of developing or worsening a disease.

The term “therapeutically effective” applied to dose or amount refers tothat quantity of a compound or pharmaceutical composition that isappropriate to result in a amelioration of existing tinnitus ortinnitus-related symptoms upon administration to a mammal in needthereof.

The phrase “pharmaceutically acceptable”, as used in connection withcompositions of the invention, refers to molecular entities and otheringredients of such compositions that are physiologically tolerable anddo not typically produce untoward reactions when administered to amammal (e.g., human). Typically, the term “pharmaceutically acceptable”means approved by a regulatory agency of the Federal or a stategovernment or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in mammals, and more particularly inhumans.

The term “carrier” applied to pharmaceutical compositions of theinvention refers to a diluent, excipient, or vehicle with which anactive compound (e.g., neramexane) is administered. Such pharmaceuticalcarriers can be sterile liquids, such as water, saline solutions,aqueous dextrose solutions, aqueous glycerol solutions, and oils,including those of petroleum, animal, vegetable or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil and the like.Suitable pharmaceutical carriers are described in “Remington'sPharmaceutical Sciences” by A. R. Gennaro, 20^(th) Edition.

The term “about” or “approximately” usually means within 20%,alternatively within 10%, including within 5% of a given value or range.Alternatively, especially in biological systems, the term “about” meanswithin about a log (i.e., an order of magnitude), including within afactor of two of a given value.

In conjunction with the methods of the present invention, also providedare pharmaceutical compositions comprising a therapeutically effectiveamount of a 1-amino-alkylcyclohexane derivative (e.g., neramexane). Thecompositions of the invention may further comprise a carrier orexcipient (all pharmaceutically acceptable). The compositions may beformulated for once-a-day administration, twice-a-day administration, orthree times a day administration.

The 1-amino-alkylcyclohexane derivative (e.g., neramexane, such asneramexane mesylate) or a pharmaceutical composition comprising the samemay be used for the treatment of tinnitus according to theadministration scheme according to the invention. In one embodiment thederivative and/or pharmaceutical composition (medicament) are adapted toor appropriately prepared for a specific administration as disclosedherein (e.g., intervallic treatment, maintenance therapy, once-a-day,twice-a-day administration, or three times a day administration). Forthis purpose the package and/or the package leaflet and/or the patientinformation and/or the dosage form itself may contain correspondinginformation.

The active ingredient (e.g., neramexane such as neramexane mesylate) orthe composition of the present invention may be used for the manufactureof a medicament for the treatment of tinnitus, wherein the medicament isadapted to or appropriately prepared for a specific administration asdisclosed herein (e.g., intervallic treatment, maintenance therapy,once-a-day, twice-a-day administration, or three times a dayadministration). For this purpose the package leaflet and/or the patientinformation contains corresponding information.

According to the present invention, the dosage form of the1-amino-alkylcyclohexane derivative (e.g., neramexane) may be a solid,semisolid, or liquid formulation according to the following.

The 1-amino-alkylcyclohexane derivatives of the present invention (e.g.,neramexane) may be administered orally, topically, parenterally, ormucosally (e.g., buccally, by inhalation, or rectally) in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers. In another embodiment for administration topediatric subjects, the 1-amino-alkylcyclohexane derivative may beformulated as a flavored liquid (e.g., peppermint flavor). The1-amino-alkylcyclohexane derivatives of the present invention may beadministered orally in the form of a capsule, a tablet, or the like, oras a semi-solid, or liquid formulation (see Remington's PharmaceuticalSciences, 20^(th) Edition, by A. R. Gennaro).

For oral administration in the form of a tablet or capsule, the1-amino-alkylcyclohexane derivatives of the present invention (e.g.,neramexane) may be combined with a non-toxic, pharmaceuticallyacceptable excipients such as binding agents (e.g., pregelatinized maizestarch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers(e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducingand non-reducing sugars, microcrystalline cellulose, calcium sulfate, orcalcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc,or silica, steric acid, sodium stearyl fumarate, glyceryl behenate,calcium stearate, and the like); disintegrants (e.g., potato starch orsodium starch glycolate); or wetting agents (e.g., sodium laurylsulphate), coloring and flavoring agents, gelatin, sweeteners, naturaland synthetic gums (such as acacia, tragacanth or alginates), buffersalts, carboxymethylcellulose, polyethyleneglycol, waxes, and the like.

The tablets may be coated with a concentrated sugar solution which maycontain e.g., gum arabic, gelatine, talcum, titanium dioxide, and thelike. Alternatively, the tablets can be coated with a polymer thatdissolves in a readily volatile organic solvent or mixture of organicsolvents. In specific embodiments, neramexane is formulated inimmediate-release (IR) or modified-release (MR) tablets. Immediaterelease solid dosage forms permit the release of most or all of theactive ingredient over a short period of time, such as 60 minutes orless, and make rapid absorption of the drug possible (immediate releaseformulations of 1-amino-alkylcyclohexanes such as neramexane aredisclosed in US Published Application Nos. 2006/0002999 and2006/0198884, the subject matter of which is hereby incorporated byreference). Modified release solid oral dosage forms permit thesustained release of the active ingredient over an extended period oftime in an effort to maintain therapeutically effective plasma levelsover similarly extended time intervals and/or to modify otherpharmacokinetic properties of the active ingredient (modified releaseformulations of neramexane are disclosed in US Published Application No.2007/0141148, the subject matter of which is hereby incorporated byreference). For example, neramexane mesylate may be formulated in amodified release dosage form (including modified release tablets) toprovide a 50 mg dose of neramexane mesylate.

For the formulation of soft gelatin capsules, the1-amino-alkylcyclohexane derivatives of the present invention (e.g.,neramexane) may be admixed with e.g., a vegetable oil or poly-ethyleneglycol. Hard gelatin capsules may contain granules of the activesubstances using either the above mentioned excipients for tablets e.g.,lactose, saccharose, sorbitol, mannitol, starches (e.g., potato starch,corn starch or amylopectin), cellulose derivatives or gelatine. Alsoliquids or semisolids of the drug can be filled into hard gelatinecapsules.

The 1-amino-alkylcyclohexane derivatives of the present invention (e.g.,neramexane) can also be introduced in microspheres or microcapsules,e.g., fabricated from polyglycolic acid/lactic acid (PGLA) (see, e.g.,U.S. Pat. Nos. 5,814,344; 5,100,669 and 4,849,222; PCT Publications No.WO 95/11010 and WO 93/07861). Biocompatible polymers may be used inachieving controlled release of a drug, include for example, polylacticacid, polyglycolic acid, copolymers of polylactic and polyglycolic acid,polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters,polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked oramphipathic block copolymers of hydrogels.

Formulation of the 1-amino-alkylcyclohexane derivatives of the presentinvention in a semi-solid or liquid form may also be used. The1-amino-alkylcyclohexane derivative (e.g., neramexane) may constitutebetween 0.1 and 99% by weight of the formulation, more specificallybetween 0.5 and 20% by weight for formulations intended for injectionand between 0.2 and 50% by weight for formulations suitable for oraladministration.

In one embodiment of the invention, the 1-amino-alkylcyclohexanederivative (e.g., neramexane) is administered in a modified releaseformulation. Modified release dosage forms provide a means for improvingpatient compliance and for ensuring effective and safe therapy byreducing the incidence of adverse drug reactions. Compared to immediaterelease dosage forms, modified release dosage forms can be used toprolong pharmacologic action after administration, and to reducevariability in the plasma concentration of a drug throughout the dosageinterval, thereby eliminating or reducing sharp peaks.

A modified release form dosage may comprise a core either coated with orcontaining a drug. The core being is then coated with a releasemodifying polymer within which the drug is dispersed. The releasemodifying polymer disintegrates gradually, releasing the drug over time.Thus, the outer-most layer of the composition effectively slows down andthereby regulates the diffusion of the drug across the coating layerwhen the composition is exposed to an aqueous environment, i.e. thegastrointestinal tract. The net rate of diffusion of the drug is mainlydependent on the ability of the gastric fluid to penetrate the coatinglayer or matrix and on the solubility of the drug itself.

In another embodiment of the invention, the 1-amino-alkylcyclohexanederivative (e.g., neramexane) is formulated in an oral, liquidformulation. Liquid preparations for oral administration can take theform of, for example, solutions, syrups, emulsions or suspensions, orthey can be presented as a dry product for reconstitution with water orother suitable vehicle before use. Preparations for oral administrationcan be suitably formulated to give controlled or postponed release ofthe active compound. Oral liquid formulations of1-amino-alkylcyclohexanes, such as neramexane, are described in PCTInternational Application No. PCT/US2004/037026, the subject matter ofwhich is hereby incorporated by reference.

For oral administration in liquid form, 1-amino-alkylcyclohexanederivatives of the present invention (e.g., neramexane) may be combinedwith non-toxic, pharmaceutically acceptable inert carriers (e.g.,ethanol, glycerol, water), suspending agents (e.g., sorbitol syrup,cellulose derivatives or hydrogenated edible fats), emulsifying agents(e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oilyesters, ethyl alcohol or fractionated vegetable oils), preservatives(e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid), and thelike. Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate,sodium ascorbate, citric acid) can also be added to stabilize the dosageforms. For example, solutions may contain from about 0.2% to about 20%by weight of neramexane, with the balance being sugar and mixture ofethanol, water, glycerol and propylene glycol. Optionally, such liquidformulations may contain coloring agents, flavoring agents, saccharineand carboxymethyl-cellulose as a thickening agent or other excipients.

In another embodiment, a therapeutically effective amount of a1-amino-alkylcyclohexane derivative (e.g., neramexane) is administeredin an oral solution containing a preservative, a sweetener, asolubilizer, and a solvent. The oral solution may include one or morebuffers, flavorings, or additional excipients. In a further embodiment,a peppermint or other flavoring is added to the neramexane derivativeoral liquid formulation.

For administration by inhalation, 1-amino-alkylcyclohexane derivatives(e.g., neramexane) of the present invention may be convenientlydelivered in the form of an aerosol spray presentation from pressurizedpacks or a nebulizer, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In thecase of a pressurized aerosol, the dosage unit can be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, e.g., gelatin for use in an inhaler or insufflator can be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

Solutions for parenteral applications by injection may be prepared in anaqueous solution of a water-soluble pharmaceutically acceptable salt ofthe active substances, e.g., in a concentration of from about 0.5% toabout 10% by weight. These solutions may also contain stabilizing agentsand/or buffering agents and may conveniently be provided in variousdosage unit ampoules.

The formulations of the invention may be delivered parenterally, i.e.,by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous(s.c.), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.),or intradermal (i.d.) administration, by direct injection, via, forexample, bolus injection or continuous infusion. Formulations forinjection can be presented in unit dosage form, e.g., in ampoules or inmulti-dose containers, with an added preservative. Alternatively, theactive ingredient may be in powder form for reconstitution with asuitable vehicle, e.g., sterile pyrogen-free water, before use.

The invention also provides a pharmaceutical pack or kit comprising oneor more containers containing a 1-amino-alkylcyclohexane derivative(e.g., neramexane) and, optionally, more of the ingredients of theformulation. In a specific embodiment, neramexane is provided as an oralsolution (2 mg/ml) for administration with the use of a 2 teaspooncapacity syringe (dosage KORC®). Each oral syringe has blue hatch marksfor measurement, with lines on the right side of the syringe (tip down)representing tsp units, and those on the left representing ml units.

The optimal therapeutically effective amount may be determinedexperimentally, taking into consideration the exact mode ofadministration, from in which the drug is administered, the indicationtoward which the administration is directed, the subject involved (e.g.,body weight, health, age, sex, etc.), and the preference and experienceof the physician or veterinarian in charge.

Dosage units for rectal application may be solutions or suspensions ormay be prepared in the form of suppositories or retention enemascomprising neramexane in a mixture with a neutral fatty base, or gelatinrectal capsules comprising the active substances in admixture withvegetable oil or paraffin oil.

Toxicity and therapeutic efficacy of the compositions of the inventionmay be determined by standard pharmaceutical procedures in experimentalanimals, e.g., by determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between therapeutic and toxic effects isthe therapeutic index and it may be expressed as the ratio LD₅₀/ED₅₀.Compositions that exhibit large therapeutic indices are preferred.

Suitable daily doses of the active compounds of the invention intherapeutic treatment of humans are about 0.01-10 mg/kg bodyweight onperoral administration and 0.001-10 mg/kg bodyweight on parenteraladministration. For example, for adults, suitable daily doses ofneramexane mesylate are within the range from about 5 mg to about 150 mgper day, such as from about 5 mg to about 120 mg, from about 5 mg toabout 100 mg, or from about 5 mg to about 75 mg, or from about 5 mg toabout 50 mg, such as 25 mg or 50 mg, per day. As a therapeuticallyeffective amount of the present invention a daily dose of neramexanemesylate may be administered within the range from about 20 mg to 150mg, such as from 25 mg to 100 mg (e.g. 30 mg, 35 mg, 40 mg, 45 mg, 50mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, or 95 mg),such as from 50 mg to 75 mg. An equimolar amount of anotherpharmaceutically acceptable salt, a solvate, an isomer, a conjugate, aprodrug or a derivative thereof, such as neramexane hydrochloride, isalso suitable. For pediatric subjects aged 4-14, neramexane (e.g.neramexane mesylate) may be administered as an oral, liquid dosage form,at about 0.5 mg/day, up to a maximum dose of 10 mg/day.

The daily doses indicated herein may be administered, for example, asone or two dosing units once, twice or three times per day. Suitabledoses per dosage unit may therefore be the daily dose divided (forexample, equally) between the number of dosage units administered perday, and will thus typically be about equal to the daily dose or onehalf, one third, one quarter or one sixth thereof. Dosages per dosageunit may thus be calculated from each daily dosage indicated herein. Adaily dose of 5 mg, for example may be seen as providing a dose perdosage unit of, for example, about 5 mg, 2.5 mg, 1.67 mg, 1.25 mg and0.83 mg, depending upon the dosing regimen chosen. Correspondingly, adosage of 150 mg per day corresponds to dosages per dosing unit of, forexample, about 150 mg, 75 mg, 50 mg, 37.5 mg, and 25 mg forcorresponding dosing regimens.

The 1-amino-alkylcyclohexane derivatives of the present invention (e.g.,neramexane) may be administered as a monotherapy, or in combination withanother agent prescribed for the treatment of tinnitus.

The term “combination” applied to active ingredients is used herein todefine a single pharmaceutical composition (formulation) comprising twoactive agents (e.g., a pharmaceutical composition comprising a1-amino-alkylcyclohexane derivative, such as neramexane, and anotheragent prescribed for the treatment of tinnitus) or two separatepharmaceutical compositions, each comprising an active agent (e.g. apharmaceutical composition comprising a 1-amino-alkylcyclohexanederivative, such as neramexane, or another agent prescribed for thetreatment of tinnitus), to be administered conjointly.

Within the meaning of the present invention, the term “conjointadministration” is used to refer to administration of1-amino-alkylcyclohexane derivative, such as neramexane, and a secondactive agent (e.g. another agent prescribed for the treatment ofcochlear tinnitus) simultaneously in one composition, or simultaneouslyin different compositions, or sequentially. For the sequentialadministration to be considered “conjoint”, however,1-amino-alkylcyclohexane derivative, such as neramexane, and the secondactive agent must be administered separated by a time interval whichstill permits the resultant beneficial effect for treating tinnitus in amammal.

EXAMPLES OF REPRESENTATIVE FORMULATIONS

With the aid of commonly used solvents, auxiliary agents and carriers,active ingredients may be processed into tablets, coated tablets,capsules, drip solutions, suppositories, injection and infusionpreparations, and the like and can be therapeutically applied by theoral, rectal, parenteral, and additional routes. Tablets suitable fororal administration may be prepared by conventional tablettingtechniques. The following example is given by way of illustration onlyand is not to be construed as limiting.

Formulation Example 1 Neramexane Mesylate Immediate Release Tablets

The following tables provide the make-up of neramexane immediate releasetablets in 12.5, 25.0, 37.5, and 50.0 mg dosages, including activecomponents, coating agents, and other excipients.

TABLE 1 Neramexane mesylate, 12.5 mg film coated tablets AmountComponent [mg] Function Neramexane mesylate 12.50 Active pharmaceuticalingredient Cellulose microcrystalline 103.25 Binder Croscarmellosesodium 6.25 Disintegrant Silicon dioxide, colloidal 1.25 Flow promoterTalc 1.25 Glident Magnesium stearate 0.50 Lubricant core weight 125.00Coating (HPMC), Opadry 5.00 Coating or Sepifilm Coat weight 5.00 coatedtablet total 130.00 weight

TABLE 2 Neramexane mesylate, 25.0 mg film coated tablets AmountComponent [mg] Function Neramexane mesylate 25.00 Active pharmaceuticalingredient Cellulose microcrystalline 206.50 Binder Croscarmellosesodium 12.5 Disintegrant Silicon dioxide, colloidal 2.50 Flow promoterTalc 2.50 Glident Magnesium stearate 1.00 Lubricant core weight 250.00Coating (HPMC), Opadry 10.00 Coating or Sepifilm Coat weight 10.00coated tablet total 260.00 weight

TABLE 3 Neramexane mesylate, 37.5 mg film coated tablets AmountComponent [mg] Function Neramexane mesylate 37.50 Active pharmaceuticalingredient Cellulose microcrystalline 309.75 Binder Croscarmellosesodium 18.75 Disintegrant Silicon dioxide, colloidal 3.75 Flow promoterTalc 3.75 Glident Magnesium stearate 1.50 Lubricant core weight 375.00Coating (HPMC), Opadry 15.00 Coating or Sepifilm Coat weight 15.00coated tablet total 390.00 weight

TABLE 4 Neramexane mesylate, 50.0 mg film coated tablets AmountComponent [mg] Function Neramexane mesylate 50.00 Active pharmaceuticalingredient Cellulose microcrystalline 413.00 Binder Croscarmellosesodium 25.00 Disintegrant Silicon dioxide, colloidal 5.00 Flow promoterTalc 5.00 Glident Magnesium stearate 2.00 Lubricant core weight 500.00Coating (HPMC), Opadry 20.00 Coating or Sepifilm Coat weight 20.00coated tablet total 520.00 weight

EXAMPLES

The following examples illustrate the invention without limiting itsscope.

Example 1 Double Blind Placebo Controlled Pilot Trial of Neramexane forTreatment of Tinnitus

The objective of this pilot project was to conduct a clinical trial toassess the efficacy of neramexane as a treatment for tinnitus. Theprimary objective of this study was to compare the efficacy,tolerability and safety of neramexane mesylate at three differentdosages (25, 50 or 75 mg/d) with placebo in subjects with subjectivetinnitus of at least moderate severity.

Study Design

In a double-blind, multicenter, randomized, placebo-controlled,parallel-group study, the efficacy of neramexane in subjects sufferingfrom tinnitus of at least moderate severity was assessed. Approximately100 patients, who fulfilled particular inclusion criteria and met noneof particular exclusion criteria, were randomized to each of fourdouble-blind treatment groups (neramexane mesylate 25, 50, 75 mg/d orplacebo), resulting in approximately 400 patients in total.

The double-blind, 16-week treatment period consisted of a 4-weekuptitration period and a 12-week fixed-dose treatment period atunchanged maintenance b.i.d. dosing. In case of poor tolerability,however, the investigator could consider a dose reduction by 25 mg/d (orplacebo, respectively). After the treatment phase, there was a 4-weekfollow-up period with no active treatment and concomitant therapyrestrictions. In total, this study involved seven study visits:screening, baseline, and at the end of weeks 4, 8, 12, 16, and 20.(Participants received either neramexane mesylate (e.g. 50 mg, as 25 mgimmediate release tablets given twice daily) or placebo twice daily for16 weeks. Neramexane mesylate was uptitrated in weekly steps of 12.5 or25 mg during a 4-week uptitration period preceding the fixed-dose12-week treatment period. Treatment was followed by a four weekfollow-up period.)

The scheduled visits for evaluation of each patient were as follows:

Visit 1 (screening): After signing the consent form, the subjectunderwent a physical examination and clinical laboratory testing.Patient eligibility for the study was evaluated via a check ofinclusion/exclusion criteria. An initial Tinnitus Interview wasconducted. The subject also completed aTinnitus-Beeinträchtigungs-Fragebogen (TBF-12) (i.e., a 12-item Germanmodified and validated version (Greimel K V et al.,Tinnitus-Beeinträchtigungs-Fragebogen (TBF-12). Manual. Frankfurt amMain: Swets & Zeitlinger B.V.; 2000) of the 25-item Tinnitus HandicapInventory or THI (Newman C W, et al. Development of the TinnitusHandicap Inventory. Arch Otolaryngol Head Neck Surg 1996; 122(2):143-148; Newman C W, et al. Psychometric adequacy of the TinnitusHandicap Inventory (THI) for evaluating treatment outcome. J Am AcadAudiol 1998; 9(2): 153-160.)), a Hospital Anxiety and DepressionScale—Depression Subscale (HADS-D) Questionnaire and a Hyperacusis(Geräuschüberempfindlichkeit-Fragenbogen (GÜF)) Questionnaire (ifapplicable).

Visit 2 (baseline): The subject was asked about adverse events andchanges in concomitant medication/disease, which events/changes weredocumented. The subject was evaluated for study eligibility based on areview of the inclusion/exclusion criteria. Trial procedures as well asallowed and forbidden concomitant medications were reviewed with thesubject. An initial Tinnitus Interview was conducted. The subject alsocompleted a TBF-12, HADS-D Questionnaire and GÜF Questionnaire (ifapplicable). The subject was enrolled in the study and study medication(placebo or neramexane) was dispensed as described below.

Visit 3 (Week 4): This visit occurred at the end of the 4-weekup-titration sequence. The subject was asked about adverse events andchanges in concomitant medication/disease, which events/changes weredocumented. A follow-up Tinnitus Interview was conducted. The subjectalso completed a TBF-12, HADS-D Questionnaire and GÜF Questionnaire (ifapplicable). Medication compliance was assessed, and medication for thenext 4 weeks was dispensed as described below.

Visit 4 (Week 8): This visit occurred at the end of the first 4-weekfixed-dose double-blind treatment period. The subject was asked aboutadverse events and changes in concomitant medication/disease, whichchanges are documented. Blood samples were collected in order todetermine neramexane pre-dose concentration. A follow-up TinnitusInterview was conducted. The subject also completed a TBF-12, HADS-DQuestionnaire and GÜF Questionnaire (if applicable). Medicationcompliance was assessed and, medication for the next 4 weeks wasdispensed as described below.

Visit 5 (Week 12): This visit occurred at the end of the second 4-weekfixed-dose double-blind treatment period. The subject was asked aboutadverse events and changes in concomitant medication/disease, whichchanges are documented. A follow-up Tinnitus Interview was conducted.The subject also completed a TBF-12, HADS-D Questionnaire and GÜFQuestionnaire (if applicable). Medication compliance was assessed and,medication for the next 4 weeks was dispensed as described below.

Visit 6 (Week 16, end of treatment): This visit occurred at the end ofthe 12-week fixed-dose double-blind treatment period. The subject wasasked about adverse events and changes in concomitantmedication/disease, which changes are documented. A clinical laboratoryevaluation was performed. A follow-up Tinnitus Interview was conducted,and the subject completed a TBF-12, HADS-D Questionnaire and GÜFQuestionnaire (if applicable). Pure-tone audiometry (air conduction) wasalso conducted.

Visit 7 (Week 20): This visit occurred at the end of the 4-weekfollow-up period after the last study medication dose. Review ofconcomitant medications as well as the occurrence of adverse eventssince the last visit is conducted with subject. A follow-up TinnitusInterview was conducted, and the subject completed a TBF-12, HADS-DQuestionnaire and GÜF Questionnaire (if applicable).

Administration of Neramexane

Neramexane mesylate immediate release tablets (12.5 mg and 25 mg) andmatching placebo tablets were administered as film coated tablets.

Medication was supplied in blister boxes that were dispensed from Visit2 to Visit 5. Each blister box contained 4 blister cards for 4 treatmentweeks and 1 blister card as reserve. Blister cards were identified bytreatment weeks. Daily medication within the blister cards wereidentified per day. Study medication for each study day consisted of 4separate tablets. One blister card contained of 32 tablets (7×4 tablets,4 tablets per day, and a reserve of 4 tablets for one day). One packageof medication per patient consisted of 5 boxes. Box 2 was added asreserve medication for box 1 (uptitration period) and was only to bedispensed if the subject lost a blister card of box 1 or the whole box.

Study medication was dispensed at Visit 2 (baseline, day 0). Eachpatient received one blister box containing 5 blister cards (includingone reserve blister) of double-blind study medication (i.e., 32tablets). Subjects were instructed to take 2 tablets twice daily (4tablets/d), beginning the day after dispensing of the study medication,until they returned for their next study visit (Visit 3). For thosesubjects assigned to receive active medication, some placebo tabletswere incorporated into the dosing regimen to ensure blinding during theuptitration period. The target fixed-maintenance dose of 25, 50, or 75mg neramexane mesylate/d was administered starting with the fifth weekof double-blind treatment and was continued throughout the study. Ateach of the subsequent visits (Visits 3, 4, and 5, corresponding to endof week 4, 8 and 12) patients received another blister box containing 5blister cards for the 4 week intervals, with double-blind medication forthe intervening treatment period until the next study visit. The dosingschedule is shown in Table 5.

Throughout the double-blind treatment period, patients were to continueto take 2×2 tablets of medication daily at a constant interval of 12hours. In case the patient had already taken the morning dose of studymedication on the day of Visits 4 and 6 (Week 8 and Week 16), noscheduled blood sampling was to be done. The investigator had tore-dispense a sufficient amount of study medication. The patient shouldcontinue to take 2 by 2 tablets at a constant interval of 12 hours andhad return for pre-dose Neramexane blood sampling within the time windowof Visits 4 and 6.

TABLE 5 Administration of Neramexane mesylate 4-week double-blind12-week fixed-dose 4-week Treatment up-titration period double-blindperiod follow-up group Week 1 Week 2 Week 3 Week 4 Weeks 5-16 Weeks17-20 High-dose 12.5/0 12.5/12.5  25/12.5 25/25 37.5/37.5 (75 mg/d) —Medium-dose 12.5/0 12.5/0   12.5/12.5  25/12.5 25/25 (50 mg/d) —Low-dose 12.5/0 12.5/0   12.5/0   12.5/0   12.5/12.5 (25 mg/d) — Placebo  0/0 0/0 0/0 0/0 0/0 — xx/xx refers to the morning/evening dose in mg,respectively

In case of poor tolerability the investigator could consider a dosereduction of 25 mg/d by omitting the bigger tablet in the morning whichconstituted an effective dose reduction only in the 75 mg/d and 50 mg/dneramexane mesylate groups. After omitting the bigger tablet (25 mg orplacebo, respectively) of the morning dose, these patients could thencontinue the course of the study as scheduled, while receiving only onesmaller tablet as the morning dose (12.5 mg or placebo, respectively)and 2 tablets of different sizes (12.5 mg, 25 mg or placebo,respectively) as the evening dose. The dose was to be kept stable untilthe end of the study.

Subjects were instructed to take study medication always at anindividually convenient, but stable time point throughout the studycourse and at a constant dosing interval of 12 hours whenever possible(e.g. 6:00 h and 18:00 h or 8:00 h and 20:00 h). At each study visit,the investigator enquired the time points of study medication intake onthe preceding day. At the end of week 4, 8, 12, and 16 (or upon earlytermination), patients returned to the study site bringing their blisterboxes containing 5 blister cards with them for an assessment ofmedication compliance.

Efficacy

Primary Outcome

-   -   The change in TBF-12 total score from baseline (Visit 2) to the        endpoint visit (Visit 6, i.e. Week 16) was the primary efficacy        endpoint in this study.

Secondary Outcomes

-   -   TBF-12 total score (values and absolute change from baseline) at        all post-baseline visits except the endpoint visit.    -   Change in the TBF-12 total score from Week 16 to Week 20 (values        and absolute changes).    -   TBF-12 factorial scores (values and absolute change from        baseline, including the change from Week 16 to Week 20) at all        post-baseline visits.    -   Hyperacusis questionnaire GÜF        (“Geräuschüberempfindlichkeits-Fragebogen”), values and absolute        change from baseline, including the change from Week 16 to Week        20, total and factorial scores at all post-baseline visits if        hyperacusis was present.    -   Clinical global impression of change: item 27 of the tinnitus        follow-up interview was summarized after dichotomization of the        responses in any improvement (values 1, 2, 3) versus no        improvement (values 4, 5, 6, 7) and in marked improvement        (values 1, 2) versus no marked improvement (values 3, 4, 5, 6,        7).    -   Total score of HADS-D as well as the depression and anxiety        subscale scores (values and absolute change from baseline, also        the change from week 16 to week 20) at all post-baseline visits.    -   Values of tinnitus interview (initial and follow-up) at all        post-baseline visits; absolute change from baseline and change        from Week 16 to Week 20 for items 8, 9, 10, 19, 20, 21, 24, 25        and 26 of the follow-up interview.

Data Analysis

All efficacy analyses were performed on the ITT population using thelast-observation-carried-forward (LOCF) approach. For sensitivitypurposes an analysis of the per-protocol set and of observed cases wasperformed additionally. All statistical tests used for testing theprimary efficacy (confirmatory testing) and secondary efficacy criteria(exploratory), and all other statistical tests used for exploratoryanalyses were two-sided hypothesis tests performed at the 5%significance level. For all variables standard descriptive statisticswere calculated.

Change from baseline (Visit 2) to Week 16 in TBF-12 total score wasanalyzed using a two-way ANCOVA model with treatment group and studycenters as factors and baseline TBF-12 total score as covariate.

For secondary efficacy parameters, the comparison between neramexane andplacebo was performed, if appropriate, by visit using a two-way ANCOVAwith treatment group and study center as factors and the correspondingbaseline value of the efficacy parameter as covariate.

Discussion

This clinical study showed promising results in terms of efficacy andsafety. After a 16-week double-blind treatment (Visit 6) with finaldaily doses of 50 or 75 mg neramexane mesylate, patients reported aclear improvement of their tinnitus, as measured by the TBF-12, whichwas distinct from the groups treated with placebo or low-dose (25 mg)neramexane mesylate. The treatment period was followed by a 4-weekwash-out period without any medication. Remarkably, subjects previouslytreated with either 50 or 75 mg neramexane mesylate reported a furtherrelevant improvement of their tinnitus which was not reported bysubjects who had received placebo or low-dose neramexane. This was anentirely unexpected clinical observation. At the end of the 4-weekwash-out (Week 20, Visit 7), differences in TBF-12 improvement betweenthe 50 mg and the placebo group reached statistical significance. Theseresults are shown in Table 6 below and in FIG. 1.

TABLE 6 Change in the TBF-12 total score from baseline to allpost-baseline visits (ITT-LOCF) Neramexane - Placebo Actual ChangeChange LSMean n Mean ± SD Mean ± SD LSMean Diff. ± SE 95% CI p-valueWeek 4 Placebo 111 13.6 ± 4.1 −0.8 ± 2.7 −0.8 n.a. n.a. n.a. 25 mg/d 10613.4 ± 4.5 −1.0 ± 2.6 −0.8 −0.1 ± 0.4 [−0.8, 0.7] 0.875 Neramexane 50mg/d 106 13.0 ± 4.7 −1.4 ± 3.2 −1.4 −0.6 ± 0.4 [−1.3, 0.1] 0.110Neramexane 75 mg/d 99 12.2 ± 4.3 −1.7 ± 2.7 −1.6 −0.9 ± 0.4  [−1.6,−0.1] 0.026 Neramexane Week 8 Placebo 111 12.5 ± 4.2 −1.9 ± 3.0 −1.8n.a. n.a. n.a. 25 mg/d 106 12.7 ± 4.9 −1.7 ± 2.9 −1.5  0.3 ± 0.4 [−0.5,1.2] 0.429 Neramexane 50 mg/d 106 12.3 ± 4.8 −2.2 ± 3.3 −2.1 −0.3 ± 0.4[−1.1, 0.5] 0.488 Neramexane 75 mg/d 99 11.9 ± 4.5 −2.0 ± 3.3 −1.9 −0.1± 0.4 [−1.0, 0.7] 0.813 Neramexane Week 12 Placebo 111 12.3 ± 4.8 −2.2 ±3.5 −2.1 n.a. n.a. n.a. 25 mg/d 106 12.8 ± 5.0 −1.6 ± 3.4 −1.4  0.6 ±0.5 [−0.3, 1.6] 0.182 Neramexane 50 mg/d 106 11.8 ± 4.9 −2.6 ± 3.8 −2.5−0.4 ± 0.5 [−1.4, 0.5] 0.357 Neramexane 75 mg/d 99 11.4 ± 4.9 −2.5 ± 3.5−2.4 −0.4 ± 0.5 [−1.3, 0.6] 0.457 Neramexane Week 16 Placebo 111 12.0 ±4.9 −2.4 ± 3.6 −2.3 n.a. n.a. n.a. 25 mg/d 106 12.4 ± 5.3 −2.0 ± 3.4−1.8  0.5 ± 0.5 [−0.5, 1.5] 0.359 Neramexane 50 mg/d 106 11.2 ± 5.1 −3.2± 4.1 −3.1 −0.8 ± 0.5 [−1.8, 0.2] 0.098 Neramexane 75 mg/d 99 11.0 ± 5.1−2.9 ± 3.9 −2.8 −0.5 ± 0.5 [−1.6, 0.5] 0.289 Neramexane Week 20(Follow-up) Placebo 101 12.0 ± 5.1 −2.6 ± 4.2 −2.5 n.a. n.a. n.a. 25mg/d 100 12.3 ± 5.5 −2.1 ± 3.4 −2.0  0.5 ± 0.6 [−0.6, 1.6] 0.336Neramexane 50 mg/d 95 10.4 ± 5.3 −3.9 ± 4.4 −3.8 −1.3 ± 0.6  [−2.4,−0.2] 0.021 Neramexane 75 mg/d 89 10.5 ± 4.9 −3.3 ± 3.6 −3.2 −0.7 ± 0.6[−1.8, 0.5] 0.244 Neramexane * LSmeans and p-values derived from anANCOVA model with treatment and center as factors and baseline TBF-12 ascovariate

These findings demonstrate that neramexane has the capability for asustained improvement of tinnitus even after the drug is withdrawn.Thus, neramexane may be useful as an interval therapy in the treatmentof tinnitus which allows for medication-free intervals without patientsexperiencing a deterioration of their tinnitus or as maintenance therapyin the treatment of tinnitus to prevent recurrence of tinnitus inpatients through administering a reduced dose of neramexane.

Example 2 Double Blind Placebo Controlled Trial of Neramexane forTreatment of Tinnitus

The objective of this project is to conduct a clinical trial to furtherassess the sustained effects of neramexane as a treatment for tinnitus.The primary objective of this study is to compare the efficacy,tolerability and safety of neramexane with placebo in subjects withfirst onset, persistent, unilateral or bilateral subjective tinnitus.

Study Design

In a double-blind, multicenter, randomized, placebo-controlled,parallel-group study, the efficacy of neramexane in subjects sufferingfrom tinnitus is assessed. Patients who fulfill particular inclusioncriteria and meet none of particular exclusion criteria are randomizedinto double-blind treatment groups.

Subjects are treated for 17 weeks with neramexane or placebo including afour-resp. five-week up-titration period, depending on study drug dose,followed by a 12-week treatment-free observational period to investigatethe sustained effects of the drug after cessation of the treatment.

Subjects with a target daily dose of 50 mg neramexane mesylate (<90 kgbody weight) will reach steady state after four weeks, patients with atarget total daily dose of 75 mg neramexane mesylate (≧90 kg bodyweight) will reach steady state after five weeks of treatment. Forpatients experiencing dose limiting adverse events with the 75 mg dose,the dosage may be reduced by switching the patient to 50 mg/day.Patients unable to tolerate a minimum dosage of 50 mg/day will bediscontinued.

The scheduled visits for evaluation of each patient are as follows:

Visit 1 (screening): After signing the consent form, the subjectundergoes a physical examination and clinical laboratory testing.Patient eligibility for the study was evaluated via a check ofinclusion/exclusion criteria.

Visit 2 (baseline): The subject is asked about adverse events andchanges in concomitant medication/disease, which events/changes aredocumented. The subject is evaluated for study eligibility based on areview of the inclusion/exclusion criteria. Trial procedures as well asallowed and forbidden concomitant medications are reviewed with thesubject. Safety and efficacy parameters are evaluated. The subject isenrolled in the study and study medication (placebo or neramexane) isdispensed as described below.

Visit 3 (Week 5): This visit occurs at the end of the up-titrationsequence. The subject is asked about adverse events and changes inconcomitant medication/disease, which events/changes are documented.Safety and efficacy parameters are evaluated. Medication is dispensed asdescribed below.

Visit 4 (Week 9): This visit occurs at the end of the first 4-weekfixed-dose double-blind treatment period. The subject is asked aboutadverse events and changes in concomitant medication/disease, whichchanges are documented. Safety and efficacy parameters are evaluated.Medication is dispensed as described below.

Visit 5 (Week 13): This visit occurs at the end of the second 4-weekfixed-dose double-blind treatment period. The subject is asked aboutadverse events and changes in concomitant medication/disease, whichchanges are documented. Safety and efficacy parameters are evaluated.Medication is dispensed as described below.

Visit 6 (Week 17, end of treatment): This visit occurs at the end of the12-week fixed-dose double-blind treatment period. The subject is askedabout adverse events and changes in concomitant medication/disease,which changes are documented. A clinical laboratory evaluation isperformed. Safety and efficacy parameters are evaluated.

Visit 7 (Week 21): This visit occurs 4 weeks after the last studymedication dose. Review of concomitant medications as well as theoccurrence of adverse events since the last visit is conducted withsubject. Safety and efficacy parameters are evaluated.

Visit 8 (Week 25): This visit occurs 8 weeks after the last studymedication dose. Review of concomitant medications as well as theoccurrence of adverse events since the last visit is conducted withsubject. Safety and efficacy parameters are evaluated.

Visit 9 (Week 29): This visit occurs at the end of the 12-week follow upperiod after the last study medication dose. Review of concomitantmedications as well as the occurrence of adverse events since the lastvisit is conducted with subject. Safety and efficacy parameters areevaluated.

Administration of Neramexane

Neramexane mesylate immediate release tablets (12.5 mg and 25 mg) andmatching placebo tablets are administered as film coated tablets.

Medication is dispensed from Visit 2 to Visit 5. Study medication foreach study day consists of 4 separate tablets. The dosing schedule isshown in Table 7.

Throughout the double-blind treatment period, patients are to continueto take 2×2 tablets of medication daily at a constant interval of 12hours.

TABLE 7 Administration of Neramexane mesylate 12-week 5-weekdouble-blind 12-week fixed-dose follow-up Treatment up-titration perioddouble-blind period Weeks group Week 1 Week 2 Week 3 Week 4 Week 5 Weeks6-17 18-29 75 mg/d dose 0/12.5 12.5/12.5 12.5/25 25/25 37.5/37.537.5/37.5 (75 mg/d) — 50 mg/d dose 0/12.5 12.5/12.5 12.5/25 25/25 25/2525/25 (50 mg/d) — Placebo 0/0   0/0  0/0 0/0 0/0 0/0 — xx/xx refers tothe morning/evening dose in mg, respectively

In case of dose limiting adverse events, the investigator could considera dose reduction of 25 mg/d only in the 75 mg/d group. Subjects unableto tolerate a minimum dosage of 50 mg/d are discontinued.

Subjects are instructed to take study medication always at anindividually convenient, but stable time point throughout the studycourse and at a constant dosing interval of 12 hours whenever possible(e.g. 6:00 h and 18:00 h or 8:00 h and 20:00 h).

Efficacy

Primary Outcome

-   -   The change in TBF-12 total score from baseline (Visit 2) to end        of treatment is the primary efficacy endpoint in this study.

Secondary Outcomes

-   -   TBF-12 and TBF-12 factorial scores (values and absolute change        from baseline) at all post-baseline visits.    -   Tinnitus loudness (11-point Likert scale).    -   Tinnitus annoyance (11-point Likert scale).    -   Tinnitus impact on life (11-point Likert scale).    -   Sum score of Tinnitus loudness, Tinnitus annoyance and Tinnitus        impact on life (T-Score).

Data Analysis

All efficacy analyses are performed on the ITT population using thelast-observation-carried-forward (LOCF) approach. All statistical testsused for testing the primary efficacy (confirmatory testing) andsecondary efficacy criteria (exploratory), and all statistical testsused for exploratory analyses are two-sided hypothesis tests performedat the 5% significance level.

Discussion

This clinical study is expected to further demonstrate that neramexanehas the capability for a sustained improvement of tinnitus even afterthe drug is withdrawn and that, therefore, neramexane may be useful asan interval therapy in the treatment of tinnitus which allows formedication-free intervals without patients experiencing a deteriorationof their tinnitus, or as maintenance therapy in the treatment oftinnitus to prevent recurrence of tinnitus in patients throughadministering a reduced dose of neramexane.

Example 3 Placebo Controlled Trial of Neramexane for Treatment ofHearing Loss Study Design

The primary objective of this study is to investigate the safety andefficacy of neramexane mesylate at daily doses of up to 75 mg in thetreatment of hearing loss in comparison to placebo.

Administration of Neramexane

Neramexane mesylate 25 mg modified release tablets and matching placebotablets are administered as film coated tablets.

Neramexane mesylate (or placebo) is uptitrated to a maximum daily doseof 75 mg, starting with a daily dose of 25 mg for one week, andincreasing dosage in 25 mg steps at weekly intervals.

Treatment is started in the evening of study day 1. The daily startingdose is 25 mg neramexane mesylate per dose to be taken for 7 days atbedtime. At day 8, the daily neramexane mesylate dose is increased to 50mg for another 7 days (two tablets in the evening for one week). At day15, patients are uptitrated to 75 mg neramexane mesylate. Patientscontinue to take neramexane for 13 weeks (three tablets once daily inthe evening for 13). Patients who do not tolerate 75 mg per day mayreduce the neramexane mesylate dose by 25 mg to 50 mg for the remainderof the total scheduled treatment duration. For example, patients who donot tolerate a 75 mg dose are allowed to step back to a 50 mg dose.Patients are then asked to stay on the 50 mg dose for the remainder ofthe total scheduled treatment duration of 7 weeks. This dosing regimenis shown in Table 8.

TABLE 8 Administration of Neramexane mesylate 2-week double-blind14-week fixed-dose 4-week Treatment uptitration period double-blindperiod follow-up group 1 2 3-16 17-20 Neramexane 0/25 0/50 0/75 mg/d —mesylate Placebo 0/0  0/0  0/0 —

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description. Suchmodifications are intended to fall within the scope of the appendedclaims.

All patents, applications, publications, test methods, literature, andother materials cited herein are hereby incorporated by reference.

1-17. (canceled)
 18. A method of treating tinnitus in a subject in needthereof, comprising administering a therapeutically effective amount ofa 1-amino-alkylcyclohexane derivative, wherein the therapeuticallyeffective amount of the 1-amino-alkylcyclohexane derivative isadministered daily for a first period of at least three (3) months,followed by a second period of at least one (1) month wherein the1-amino-alkylcyclohexane derivative is administered at a dose which is0-75% of the therapeutically effective dose.
 19. The method of claim 18,wherein during the second period the 1-amino-alkylcyclohexane derivativeis administered at a dose which is above 0-75% of the therapeuticallyeffective dose.
 20. The method of claim 18, wherein during the secondperiod the 1-amino-alkylcyclohexane derivative is administered at a dosewhich is 20-75% of the therapeutically effective dose.
 21. The method ofclaim 18, wherein during the second period the 1-amino-alkylcyclohexanederivative is administered at a dose which is 25-50% of thetherapeutically effective dose.
 22. The method of claim 18, whereinduring the second period the 1-amino-alkylcyclohexane derivative is notadministered with treatment being repeated after the second period. 23.The method of claim 18, wherein a dose increase to reach atherapeutically effective dose following the second period is performedstepwise.
 24. The method of claim 18, wherein the second period isfollowed by administering to the subject a therapeutically effectiveamount of a 1-amino-alkylcyclohexane derivative after a recurrence oftinnitus.
 25. The method of claim 24, wherein the administration of thetherapeutically effective amount of a 1-amino-alkylcyclohexanederivative after recurrence of tinnitus is continued for at least oneyear.
 26. The method of claim 18, wherein the second period is fromthree (3) to six (6) months.
 27. The method of claim 18, wherein betweenthe first and second period there is a transition period during whichthe dose is reduced stepwise.
 28. The method of claim 18, wherein the1-amino-alkylcyclohexane derivative is neramexane or a pharmaceuticallyacceptable salt thereof.
 29. The method of claim 28, wherein the1-amino-alkylcyclohexane derivative is neramexane mesylate.
 30. Themethod of claim 29, wherein neramexane mesylate is administered in arange from about 5 mg to about 150 mg/day during the first period. 31.The method of claim 29, wherein neramexane mesylate is administered in arange from about 5 mg to about 100 mg/day during the first period. 32.The method of claim 29, wherein neramexane mesylate is administered in arange from about 5 mg to about 75 mg/day during the first period. 33.The method of claim 29, wherein neramexane mesylate is administered atabout 50 mg/day during the first period.
 34. The method of claim 29,wherein neramexane mesylate is administered at about 75 mg/day duringthe first period.
 35. The method of claim 28, wherein neramexane or apharmaceutically acceptable salt thereof is administered once a day,twice a day (b.i.d.), or three times a day.
 36. The method of claim 35,wherein neramexane or a pharmaceutically acceptable salt thereof isadministered twice a day.
 37. The method of claim 28, wherein neramexaneor a pharmaceutically acceptable salt thereof is administered in animmediate release formulation.
 38. The method of claim 28, whereinneramexane or a pharmaceutically acceptable salt thereof is administeredin a modified release formulation.
 39. A method of treating a1-amino-alkylcyclohexane derivative responsive condition in a subject inneed thereof, comprising administering a therapeutically effectiveamount of a 1-amino-alkylcyclohexane derivative, wherein thetherapeutically effective amount of the 1-amino-alkylcyclohexanederivative is administered daily for a first period of at least three(3) months, followed by a second period of at least one (1) monthwherein the 1-amino-alkylcyclohexane derivative is administered at adose which is 0-75% of the therapeutically effective dose.